Rescue of exhausted CD8 T cells by PD-1 targeted therapies is CD28-dependent

By A. Kamphorst, A. Wieland, T. Nasti, Shu Yang, Ruan Zhang, Daniel L. Barber, B. Konieczny, Candace Z. Daugherty, Lydia Koenig, Ke Yu and 10 more. Science, 2017

903 citations recorded by the source corpus.

Immunotherapeutic PD-1–targeted therapies require CD28 to promote cancer cell killing. CD28 is a critical target for PD-1 blockade PD-1–targeted therapies have been a breakthrough for treating certain tumors and can rejuvenate T cells to unleash the anticancer immune response (see the Perspective by Clouthier and Ohashi). It is widely believed that PD-1 suppresses signaling through the T cell receptor (TCR). However, Hui et al. find instead that the TCR costimulatory receptor, CD28, is the primary target of PD-1 signaling. Independently, Kamphorst et al. show that CD28 is required for PD-1 therapies to kill cancer cells efficiently and eliminate chronic viral infections in mice. Lung cancer patients that responded to PD-1 therapy had more CD28+ T cells, which suggests that CD28 may predict treatment response. Science, this issue p. 1428, p. 1423; see also p. 1373 Programmed cell death–1 (PD-1)–targeted therapies enhance T cell responses and show efficacy in multiple cancers, but the role of costimulatory molecules in this T cell rescue remains elusive. Here, we demonstrate that the CD28/B7 costimulatory pathway is essential for effective PD-1 therapy during chronic viral infection. Conditional gene deletion showed a cell-intrinsic requirement of CD28 for CD8 T cell proliferation after PD-1 blockade. B7-costimulation was also necessary for effective PD-1 therapy in tumor-bearing mice. In addition, we found that CD8 T cells proliferating in blood after PD-1 therapy of lung cancer patients were predominantly CD28-positive. Taken together, these data demonstrate CD28-costimulation requirement for CD8 T cell rescue and suggest an important role for the CD28/B7 pathway in PD-1 therapy of cancer patients.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/4a5ee80314b0193d453595b40024fb6601852cbe

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Citations in the corpus

CD8 T Cell Exhaustion During Chronic Viral Infection and Cancer. (2019, background): “Further, CD28 was shown to be essential for effective PD1 blockade therapy during chronic LCMV infection and in mouse tumor models, since conditional deletion of CD28 diminished the efficacy of PD-1 pathway blockade (111).”
Neoadjuvant checkpoint blockade for cancer immunotherapy (2020, background): “reported that tumor killing by reinvigorated intratumoral tumor-specific T cells after PD1 blockademay enable de novo T cell priming against new epitopes (46).”
T Cell Dysfunction in Cancer (2018, background): “Furthermore, the effect of PD-1 blockade was abrogated by conditional gene deletion of CD28 in a mouse model of chronic infection (Kamphorst et al., 2017), indicating that the CD28/B7 pathway may play a crucial role in the efficacy of anti-PD-1 treatment.”
Proliferation of PD-1+ CD8 T cells in peripheral blood after PD-1–targeted therapy in lung cancer patients (2017, background): “We recently reported on the importance of CD28 engagement for expansion of PD-1+ CD8 T cells during PD-1–targeted therapy (18), but the role of other costimulatory molecules still needs to be addressed.”
Anti-PD-1 and Anti-CTLA-4 Therapies in Cancer: Mechanisms of Action, Efficacy, and Limitations (2018, background): “Two recent studies have shown that it is indeed CD28-expressing cells rather than already terminally differentiated effector cells that respond to PD-1 blockade with a proliferative burst and differentiation (94, 95).”